美國麻省理工學(xué)院科學(xué)家近日通過研究,，發(fā)現(xiàn)了鐵循環(huán)的關(guān)鍵蛋白,。這一發(fā)現(xiàn)將有助于為β-地中海貧血病等遺傳血液病提供新的治療手段,。相關(guān)論文10月11日在線發(fā)表于《臨床檢查雜志》（Journal of Clinical Investigation）上,。
此次研究由麻省理工學(xué)院（MIT）哈佛－麻省理工健康科學(xué)與技術(shù)部（HST）的科學(xué)家Jane-Jane Chen領(lǐng)導(dǎo)完成,。兩年前,，她和研究小組發(fā)現(xiàn)，一種真核轉(zhuǎn)錄起始因子蛋白激酶（HRI）能夠使患有β-地中海貧血病的小鼠保持存活,。之后研究表明,，HRI能夠最大化減少球蛋白鏈反常的、有毒的不穩(wěn)定性,，這對(duì)紅血球中的血色素來說至關(guān)重要,。血色素的作用在于將氧輸入身體器官并將二氧化碳帶走。
在最新的研究中,，Chen和研究小組發(fā)現(xiàn),，當(dāng)小鼠體內(nèi)缺乏HRI時(shí)，鐵循環(huán)就會(huì)變慢,，結(jié)果導(dǎo)致制造紅血球的鐵離子變少,。
研究人員通過進(jìn)一步的研究揭示了HRI作用于鐵循環(huán)的深層機(jī)制。首先,，缺乏HRI會(huì)導(dǎo)致另一種蛋白－h(huán)epcidin的含量降低,，而hepcidin是鐵循環(huán)的主要調(diào)控者，它會(huì)釋放身體內(nèi)貯存的鐵并使其能夠進(jìn)入血色素，缺乏hepcidin,，身體內(nèi)貯存的鐵就無法得到有效利用,。
另外，研究人員發(fā)現(xiàn),，HRI主要是在巨噬細(xì)胞中進(jìn)行表達(dá),。一旦身體缺乏HRI，巨噬細(xì)胞就無法發(fā)揮正常的功能,，也就是無法吞噬“垂死”的紅血球并釋放出鐵,，這樣一來，紅血球死亡后就會(huì)通過腎臟排出體外,，造成身體鐵的凈損失,。
根據(jù)這一發(fā)現(xiàn)，Chen目前正和研究小組進(jìn)行一項(xiàng)新的研究,，希望找出能夠調(diào)控HRI信號(hào)路徑的分子,。“也許我們將發(fā)現(xiàn)某種化合物，它能夠幫助治療β-地中海貧血病以及其它HRI起作用的疾病”,，她說,。（科學(xué)時(shí)報(bào)）
原始出處:
J. Clin. Invest. doi:10.1172/JCI32084.
The function of heme-regulated eIF2 kinase in murine iron homeostasis and macrophage maturation
Sijin Liu1, Rajasekhar N.V.S. Suragani1, Fudi Wang2, Anping Han1, Wanting Zhao1, Nancy C. Andrews2 and Jane-Jane Chen1
1Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 2Division of Hematology/Oncology, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Jane-Jane Chen, E25-545, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. Phone: (617) 253-9674; Fax: (617) 253-3459; E-mail: [email protected] .
Received for publication March 9, 2007, and accepted in revised form July 18, 2007.
Heme-regulated eIF2 kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and ß-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri–/– mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri–/– mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri–/– mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri–/– macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
